The proposed research is an extension of ongoing studies on the plasticity of the nervous system during development, maturity and old age. Using molecular genetic, immunocytochemical, biochemical and pharmacologic techniques, we have found that extracellular signals regulate neurotransmitter metabolism, and may actually alter neurotransmitter phenotypic expression by neurons during development and maturity. We have begun to define trans-synaptic molecular messages and their trophic effects in the neonate and adult nervous system. We are now using in vivo and tissue culture approaches to define the specific molecular messages that govern neurotransmitter plasticity throughout life. The present studies will focus on the molecular mechanisms regulating neuronal plasticity in the peripheral nervous system and brain. More specifically, we hope to a) define molecular genetic mechanisms underlying phenotypic plasticity in neonatal sympathetic neurons, using cDNA probes; b) define the scope and basis of plasticity in adult neurons; c) determine the basis of deficits in plasticity that we have recently defined in aged neurons; d) define molecular genetic mechanisms underlying trans-synaptic regulation of transmitter development, and trans-synaptic regulation of transmitter enzymes during maturity; e) define molecular genetic mechanisms underlying independent regulation of different neurohumoral systems within the same cell, using cDNA to proenkephalin and tyrosine hydroxylase in the adrenal medulla; f) determine how neuronal aggregation alters transmitter phenotypic expression; g) define mechanisms by which nerve growth factor regulates development and maintenance of specific subpopulations of brain neurons, a recent finding in our laboratory. These studies then are directed toward understanding neuronal and synaptic plasticity at the molecular level.